Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-30
2001-09-25
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S187000, C546S189000
Reexamination Certificate
active
06294554
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to amide derivatives of 1,4-di-substituted piperidines useful in the treatment of cognitive disorders, pharmaceutical compositions containing the compounds, methods of treatment using the compounds, and to the use of said compounds in combination with acetylcholinesterase inhibitors.
Alzheimer's disease and other cognitive disorders have received much attention lately, yet treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially in relation to M1 muscarinic receptors, should possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) disclose 3-&agr;-chloroimperialine as a highly selective m2 muscarinic antagonist.
Piperidine-derivative muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease are disclosed in WO96/26196 and WO98/05292. In particular, WO98/05292 discloses compounds of the generic formula
wherein, inter alia, Y is CH; Z is N; X is —SO
2
—; R is substituted phenyl; R
1
and R
21
are each H, or together form an ethylenedioxy group; R
3
, R
4
, R
26
and R
27
are hydrogen; and R
2
is a N-substituted 4-piperidine derivative, wherein the N-substituent can be an amino-substituted benzoyl or pyridinecarboxyl group. Similar compounds wherein the benzene ring is replaced by a pyridinyl ring are disclosed in PCT/US99/12821. Compounds of the present invention represent a selection invention over WO98105292 and PCT/US99/12821.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the structural formula I
or a pharmaceutically acceptable salt, ester or solvate thereof, wherein
Q and Q
1
are each —CH═, or one of Q and Q
1
is —CH═and the . other is —N═;
X is —CH
2
— or
Y and Z are independently selected from the group consisting of—C(R
5
)═, or one of Y and Z is —C(R
5
)═ and the other is —N═;
R
1
is 1 to 3 substituent independently selected from the group consisting of H, halogen and (C
1
-C
6
)allkoxy;
R
2
and R
5
are independently 1 to 3 substituents independently selected from the group consisting of H. halogen, (C
1
-C
6
)alkyl and (C
1
-C
6
)alkoxy; and
R
3
and R
4
are independently selected from the group consisting of H and (C
1
-C
6
)alkyl.
One group of preferred compounds is that wherein both Y and Z are —C(R
5
)═, wherein R
5
is preferably H, methyl or halogen, Also preferred are compounds wherein Y is —CH═, Z is —N═ and R
2
is hydrogen.
R
1
is preferably halogen, more preferably chloro, or methoxy. In particular, R
1
is 3-chloro or 4-methoxy.
Q and Q
1
are preferably each —CH═.
Preferred R
2
substituents are Cl, F and methyl; 3-methyl is more preferred.
R
3
and R
4
are preferably each H.
Compared to the compounds specifically disclosed in WO98/05292 or PCT/US99112821, none of which contain the 2-amino-benzamide (i.e., anthranilamide) or the 2-aminopyridincarboxamide moiety, compounds of the present invention show surprisingly greater selectivity for the m2 receptor, and also show improved oral absorption and in vivo efficacy.
In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier. The invention also relates to a method of using a compound of formula I or a pharmaceutical composition comprising a compound of formula I in the treatment of a cognitive disease or neurodegenerative disease comprising administering an effective amount of a compound or composition of this invention to a mammal in need of such treatment.
In still another aspect, the invention relates to a method for treating a cognitive disease or neurodegenerative disease comprising administering to a mammal in need of such treatment an effective amount of a combination of a compound of formula I and an acetylcholinesterase inhibitor.
In a final aspect, the invention relates to a kit for treating a cognitive disease or neurodegenerative disease comprising in separate containers in a single package pharmaceutical compositions for use in combination, in one container a compound of formula I in a pharmaceutically acceptable carrier and in a second container, an acetylcholinesterase inhibitor in a pharmaceutically acceptable carrier, the combined quantities being an effective amount.
DETAILED DESCRIPTION
As used herein, halogen represents fluoro, chloro, bromo or iodo.
When a variable appears more than once in the structural formula, for example when R
1
is two or three substituents, the identity of each variable appearing more than once may be independently selected from the definitions for that variable.
Compounds of formula I can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.
A compound of formula I may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.
Compounds of formula I can be prepared using methods well known to those skilled in the art, for example by procedures disclosed in WO98/05292. The skilled artisan will recognize that other procedures may be applicable, and that the procedures may be suitably modified to prepare other compounds within the scope of formula I.
Compounds of formula I as defined above are preferably prepared as shown in the following reaction schemes (abbreviations used in the schemes and descriptions are defined below). In general, compounds of formula I are prepared by coupling an amine of formula II with an anthranilic or nicotinic acid of formula III:
The reaction is carried out using methods well known in the art, such as by treatment of the amine II with the acid III and a dehydrating agent such as EDCI and HOBt in the presence of a base such as N-methyl-morpholine, in a solvent such as CH
2
Cl
2
or DMF.
Starting materials of formula II are made by various processes known in the art. In the following reaction schemes, typical procedures and reagents are shown for preparing the starting materials, although those skilled in the art will recognize that preparation of the compounds of the invention is not limited to these procedures or reagents.
Compounds of formula IIa wherein Q and Q
1
are each —CH═ and X is —CH
2
— can be made according to Scheme A:
Compounds of formula IIb wherein Q and Q
1
are each —CH═, R
1
is
can be made according to Scheme B:
Compounds of formula IIc wherein Q and Q
1
are each —CH═, R
1
is
can be made according to Scheme C,
This process comprises essentially the same procedures as in Scheme B, but reverses the order of attaching the phenylsulfonyl fluoride and the piperidone.
Starting materials of formula IId wherein X is —CH
2
—, Q is —CH═ and Q
1
is —N═ can be made according to Scheme D:
Starting materials of formula IIe wherein X is —CH
2
—, Q is —N═ and Q
1
is —CH═ can be made according to Scheme E:
Scheme E
Alternatively
Clader John W.
Kozlowski Joseph A.
McCombie Stuart W.
Miller Michael W.
Vice Susan F.
Aulakh Charanjit S.
Magatti Anita W.
Schering Corporation
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